Improvements in technology of the major imaging approaches have lead to advances in the clinic as well as in novel experimental approaches to investigate oncologic and normal biological processes at both the anatomical and molecular levels. In particular, the use of reporter genes in gene therapy vectors combined with imaging has allowed one to follow the progression of cancer in living animals without the need for surgical biopsy. One of the limitations in use of reporter genes is the inability to target the gene vector to the specific tumor directly within the host. The best vector would be one that can transduce tumor cells and maintain stable transduction and long-term expression. Ideally, this would be accomplished by direct injection into the bloodstream followed by homing of the vector to the tumor cells. Retroviral vectors and specifically lentiviral vectors are most suitable for this purpose since they will infect and stably integrate into host cell genome. Among retroviruses, lentiviruses are particularly useful since they can infect non or slowly dividing cells and therefore have been used for direct injection of tissues. There have been numerous previous attempts at modification of retroviral envelope for targeting purposes, but in general resulted in low viral titers and inconsistent specificity. For the first time we have successfully engineered a retroviral vector, both lentiviral and oncoretroviral, that can be utilized to retarget the specificity of the vectors to specific cell surface molecules. Of particular importance, these vectors have high specificity while maintaining high viral titers. In our recent published model system we demonstrated that intravenous injection of the vectors will lead to specific targeting of human P-glycoprotein expressed on the surface of metastatic melanoma in a mouse model. Together with this targeting vector, we believe that we can now take full advantage of the major advances in imaging technologies for cancer to develop novel approaches to address experimental questions in animals and in the future to improve diagnostic approaches in patients. The proposed studies address fundamental questions regarding the mode of action of the targeting vector and its utility for molecular imaging.